# Brain organoid modeling of Gaucher disease for identification of pathogenic pathways and therapy development

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $238,500

## Abstract

Project Summary:
The objective of this application is to establish a human brain organoid model of Gaucher disease (GD) for
identification of pathological targets and testing of novel therapies. GD is an inherited lysosomal storage disease
and included in newborn screening programs. Prevalence of GD is 1/50,000 live births in the general population.
In GD, mutations in the coding region of the acid beta-glucosidase (GCase) gene, GBA1, result in progressive
glycosphingolipid substrate accumulation and a continuum of clinical phenotypes in visceral organs and central
nervous system (CNS). GD is classified as visceral (Type 1) or neuronopathic (Types 2 and 3) diseases. Typical
manifestations of GD Type 1 include visceral, hematologic and bone diseases that are treated with enzyme
replacement therapy or substrate reduction therapy. Type 2 is an acute, rapidly progressive neonatal CNS
disease with no treatment available leading to death by 2 years. Type 3 is a subacute, progressive CNS and
visceral disease presenting in childhood with potential survival into the 2nd to 5th decades with death caused by
untreatable CNS disease. Neuronopathic GD (nGD) affects the CNS through progressive neurodegeneration
and inflammation, leading to significant functional deficits and mortality. Newborn screening programs now
facilitate diagnosis of presymtomatic newborns and treatment initiation before significant disease progression.
However, no effective treatment for nGD exists. A major roadblock in identifying novel therapeutic options for
nGD is the absence of a human experimental system faithfully recapitulating complex neural tissues. Traditional
two-dimensional cell cultures and animal models have limitations in modeling complex brain tissues and faithfully
mirroring human disease, respectively. In this application, we aim to establish a human brain organoid model of
nGD for identification of pathological targets and future therapy development. We have successfully generated
brain organoids from human nGD induced pluripotent stem cells (iPSCs) and created isogenic control iPSCs by
genetic correction of the GBA1 mutation. Furthermore, we have confirmed the nGD phenotype and identified
dysregulated pathways in nGD iPSCs and iPSC-derived neural precursor cells. These preliminary studies
establish the feasibility of brain organoid modeling of nGD and support our hypothesis that nGD iPSC-derived
brain organoids will exhibit GD-relevant phenotypes and provide a platform for studying GD pathogenesis and
testing therapies. In this proposal, we will generate and characterize brain organoids derived from human nGD
iPSCs, validate nGD phenotypes and identify dysregulated pathways (Aim 1). Furthermore, we will test a
therapeutic approach of substrate reduction therapy in nGD brain organoids and determine anti-nGD effects and
safety in a human disease-relevant brain model (Aim 2). The generation of 3D brain organoids provides a
physiologically-relevant system for study of hu...

## Key facts

- **NIH application ID:** 10042957
- **Project number:** 1R21HD102788-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Ying Sun
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $238,500
- **Award type:** 1
- **Project period:** 2020-09-08 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042957

## Citation

> US National Institutes of Health, RePORTER application 10042957, Brain organoid modeling of Gaucher disease for identification of pathogenic pathways and therapy development (1R21HD102788-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10042957. Licensed CC0.

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